ACTR-14. A PROSPECTIVE RANDOMIZED STUDY OF CONCURRENT CHEMORADIOTHERAPY WITH TEMOZOLOMIDE VERSUS RADIOTHERAPY ALONE IN PATIENTS WITH IDH WILD-TYPE/TERT PROMOTER MUTATION GRADE II/III GLIOMAS
ABSTRACT: Abstract Our previous data showed that WHO grade II/III gliomas with isocitrate dehydrogenase wide-type (IDH-wt) and telomerase reverse transcriptase promoter mutation (TERTp-mut) have dismal prognosis as glioblastoma. This study compared concurrent chemoradiotherapy(CRT) with radiotherapy(RT) alone on the outcome of these patients. Between September 2016 and November 2018, 30 eligible grade II/III glioma patients with IDH-wt and TERTp-mut were randomly assigned to receive either RT (60 Gy in 30 daily fractions for 6 weeks) alone (n=15) or concurrent CRT with daily temozolomide and adjuvant temozolomide (n=15). The median follow-up duration was 15.5 months. The median age was 51 years (range, 24–66 years). The median Karnofsky performance status (KPS) score at randomization was 80 (range, 60–80). Surgery was the primary treatment. The characteristics of the two treatment groups were well balanced at baseline. The 1-year OS rate was significant difference between CRT group (92.3%; 95% CI: 77.8–100) and RT alone group(71.1%; 95% CI: 47.0–95.2) (p = 0.019). Local, distant, and combined tumor recurrence patterns were observed in 4 (26.7%), 1 (6.7%), and 3 patients (20%) in the CRT group and 4 (26.7%), 3 (20%), and 3 patients (20%) in the RT alone group. Those treated with RT alone had shorter median PFS (9 vs 18 months, HR: 0.517; 95% CI: 0.193 to 1.386; p = 0.19). CRT with temozolomide and extent of resection were statistically significant predictors for survival on univariate analysis. Multivariate analysis showed that CRT was associated with a significantly better OS compared with RT alone (OR=0.195; 95% CI, 0.044 to 0.867; p=0.032). Consequently, concurrent CRT with daily temozolomide and adjuvant temozolomide for newly diagnosed IDHwt/TERTp-mut grade II/III gliomas had significantly better OS compared with RT alone. A large multi-center prospective randomized trial is warranted. The trial has been registered at ClinicalTrials.gov (NCT02766270).
Project description:The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter.We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype.TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation.In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.
Project description:Grade II and III gliomas have variable clinical behaviors, showing the distinct molecular genetic alterations from glioblastoma (GBM), many of which eventually transform into more aggressive tumors. Since the classifications of grade II/III gliomas based on the genetic alterations have been recently emerging, it is now a trend to include molecular data into the standard diagnostic algorithm of glioma.Here we sequenced TERT promoter mutational status (TERTp-mut) in the DNA of 377 grade II/III gliomas and analyzed the clinical factors, molecular aberrations, and transcriptome profiles.We found that TERTp-mut occurred in 145 of 377 grade II and III gliomas (38.5%), mutually exclusive with a TP53 mutation (TP53-mut; P < .001) and coincident with a 1p/19q co-deletion (P = .002). TERTp-mut was an independent predictive factor of a good prognosis in all patients (P = .048). It has been an independent factor associated with a good outcome in the IDH mutation (IDH-mut) subgroup (P = .018), but it has also been associated with a poor outcome in the IDH wild-type (IDH-wt) subgroup (P = .049). Combining TERTp-mut and IDH-mut allowed the grade II/III malignancies to be reclassified into IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt. 1p/19q co-deletion, TP53-muts, Ki-67 expression differences, and p-MET expression differences characterized IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt subtypes, respectively.Our results showed that TERTp-mut combined with IDH-mut allowed simple classification of grade II/III gliomas for stratifying patients and clarifying diagnostic accuracy by supplementing standard histopathological criteria.
Project description:BACKGROUND:Patients with low-grade gliomas (LGGs) with isocitrate dehydrogenase (IDH) mutation (mut) and 1p19q codeletion (codel) have a median overall survival of longer than 10?years. The aim of this study is to assess the role of postsurgical treatments. SUBJECTS, MATERIALS, AND METHODS:We evaluated patients with LGGs with IDH mut and 1p19q codel; IDH1/2 was performed by immunohistochemistry and quantitative polymerase chain reaction. In all wild-type cases, we performed next-generation sequencing. 1p19 codel analysis was performed by fluorescence in situ hybridization. RESULTS:Among the 679 patients, 93 with LGGs with IDH mutation and 1p19q codel were included. Median follow-up (FU) was 96.1?months. Eighty-four patients (90.3%) were high risk according to Radiation Therapy Oncology Group criteria. After surgery, 50 patients (53.7%) received only FU, 17 (18.3%) chemotherapy (CT), and 26 (30.1%) radiotherapy (RT) with (RT?+?CT, 8 patients, 8.6%) or without (RT, 18 patients, 19.4%) chemotherapy. Median progression-free survival (mPFS) was 46.3?months, 50.8 months, 103.6?months, and 120.2?months in patients with FU alone, with CT alone, with RT alone, or with RT?+?CT, respectively. Median PFS was significantly longer in patients who received postsurgical treatment (79.5?months, 95% confidence interval [CI]: 66.4-92.7) than patients who received FU (46.3 months, 95% CI: 36.0-56.5). Moreover, mPFS was longer in patients who received RT (alone or in combination with CT, n?=?26, 113.8 months, 95% CI: 57.2-170.5) than those who did not (n?=?67, 47.3?months, 95% CI: 36.4-58.2). In particular, temozolomide alone did not improve PFS with respect to FU. CONCLUSION:RT with or without chemotherapy, but not temozolomide alone, could extend PFS in IDH mut 1p19q codel LGGs. IMPLICATIONS FOR PRACTICE:Low-grade gliomas with high-risk features, defined according to Radiation Therapy Oncology Group criteria, receive radiotherapy and/or chemotherapy as postsurgical treatments. Radiotherapy, however, has serious long-term effects (cognitive impairment), which are to be taken into account in these young patients. Moreover, low-grade gliomas with isocitrate dehydrogenase mutation and 1p19q codeletion (oligodendrogliomas) have an extremely long survival and a better prognosis. This study suggests that postsurgical treatments prolong the time before tumor progression in patients with good prognosis as well as those with oligodendroglioma. Moreover, temozolomide alone might not be effective in prolonging progression-free survival.
Project description:The promoter region of telomerase reverse transcriptase (TERTp) and isocitrate dehydrogenase (IDH) have been regarded as biomarkers with distinct clinical and phenotypic features. Investigated the possible correlations between tumor location and genetic alterations would enhance our understanding of gliomagenesis and heterogeneity of glioma. We examined mutations of TERTp and IDH by direct sequencing and fluorescence in-situ hybridization in a cohort of 225 grades II and III diffuse gliomas. Correlation analysis between molecular markers and tumor locations was performed by Chi-square tests/Fisher's exact test and multivariate logistic regression analysis. We found gliomas in frontal lobe showed higher frequency of TERTp mutation (P=0.0337) and simultaneously mutations of IDH and TERTp (IDH (mut)-TERTp(mut)) (P=0.0281) than frequency of biomarkers mutation of tumors in no-Frontal lobes, while lower frequency of TERTp mutation (P<0.0001) and simultaneously wild type of IDH and TERTp (IDH (wt)-TERTp(wt)) (P<0.0001) in midline than no-midline lobes. Logistic regression analysis indicated that locations of tumors associated with TERTp mutation (OR=0.540, 95% CI 0.324-0.900, P=0.018) and status of combinations of IDH and TERTp (IDH (mut)-TERTp (mut) vs. IDH (wt)-TERTp (wt) OR=0.162, 95% CI 0.075-0.350, P<0.001). In conclusion, grades II and III gliomas harboring TERTp mutation were located preferentially in the frontal lobe and rarely in midline. Association of IDH-TERTp status and tumor location suggests their potential values in molecular classification of grades II and III gliomas.
Project description:PURPOSE:Patients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT. PATIENTS AND METHODS:Using trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT. RESULTS:IDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT. CONCLUSION:IDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.
Project description:We report on the long-term results of a phase II study of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma. Pre-RT temozolomide was given for up to 6 cycles. RT with concurrent temozolomide was administered to patients with less than a complete radiographic response. Forty eligible patients were entered and 32 completed protocol treatment. With a median follow-up time of 8.7 years (range 1.1-10.1), median progression-free survival (PFS) is 5.8 years (95 % CI 2.0, NR) and median overall survival (OS) has not been reached (5.9, NR). 1p/19q data are available in 37 cases; 23 tumors had codeletion while 14 tumors had no loss or loss of only 1p or 19q (non-codeleted). In codeleted patients, 9 patients have progressed and 4 have died; neither median PFS nor OS have been reached and two patients who received only pre-RT temozolomide and no RT have remained progression-free for over 7 years. 3-year PFS and 6-year OS are 78 % (95 % CI 61-95 %) and 83 % (95 % CI 67-98 %), respectively. Codeleted patients show a trend towards improved 6-year survival when compared to the codeleted procarbazine/CCNU/vincristrine (PCV) and RT cohort in RTOG 9402 (67 %, 95 % CI 55-79 %). For non-codeleted patients, median PFS and OS are 1.3 and 5.8 years, respectively. These updated results suggest that the regimen of dose intense, pre-RT temozolomide followed by concurrent RT/temozolomide has significant activity, particularly in patients with 1p/19q codeleted AOs and MAOs.
Project description:BACKGROUND:It has been reported that radiation therapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy could improve progression-free survival (PFS) and overall survival (OS) in patients with high-risk World Health Organization (WHO) grade 2 gliomas after surgery. However, procarbazine is not available in China. In clinical practice, Chinese doctors often use radiotherapy combined with temozolomide (TMZ) to treat these patients, although large-scale prospective studies are lacking. This trial aims to confirm whether RT combined with temozolomide can improve PFS and OS in high-risk patients with low-grade gliomas (LGGs). METHODS/DESIGN:This is a two-group, randomized controlled trial (RCT) enrolling patients who have LGGs (WHO grade 2) and are aged 40?years or older without regard to the extent of resection or are aged younger than 40?years old with subtotal resection or biopsy. An estimated 250 patients will be enrolled. Eligible participants will be randomly assigned to receive RT alone or RT plus TMZ chemotherapy in a 1:1 ratio. The same RT will be given to all eligible participants regardless of whether they are randomly assigned to the RT group or the chemoradiotherapy (CRT) group. While in the CRT group, patients will receive adjuvant TMZ with or without concurrent radiochemotherapy. The primary outcome of this trial is PFS, and it will be analyzed by the intention-to-treat approach. Secondary outcomes include OS, adverse events, and cognitive function. DISCUSSION:The objective of our research is to assess the effect of radiotherapy coupled with TMZ in high-risk patients with LGGs after surgery, compared with RT alone. Different histological types and molecular subtypes will be examined, and a corresponding subgroup analysis will be conducted. Our data can provide evidence for postoperative adjuvant therapy in patients with high-risk LGGs in China. TRIAL REGISTRATION:Chinese Clinical Trial Registry, ChiCTR1800015199. Registered on 13 March 2018.
Project description:The optimal treatment for stage I squamous cell carcinoma of the anus (SCCA) remains undefined. Recently, wide local excision alone was found to have comparable survival to those treated with chemoradiation (CRT). Given that local excision may be sufficient for the treatment of stage I SCCA, we hypothesized that radiation therapy (RT) alone, compared to CRT would result in equivalent overall survival (OS) in this population. We identified non-surgically treated patients with stage I SCCA from the National Cancer Database from 2004-2015. We included only patients treated either with CRT (45-59.4 Gy with chemotherapy initiated within 14 days of RT) or RT alone (45-59.4 Gy with no chemotherapy). The primary endpoint was OS between CRT and RT patients. Propensity-score matched (PSM) analysis was performed to determine the effect of concurrent chemotherapy on OS using a Cox proportional hazards model with robust standard error to account for clustering in matched pairs. We identified 3552 stage I patients treated with CRT and 287 treated with RT. Compared to patients treated with CRT, those that received RT were more likely to be ?70 years old (33.1% vs. 19.7%, p < 0.001) and less likely to be female (63.1% vs. 71.0%, p < 0.001). The proportion of patients with a Charlson-Deyo score of 0 was similar in both groups (80.8% RT vs. 82.7% CRT, p = 0.164). The PSM cohort consisted of 287 pairs of patients with median follow-up 48.3 months (interquartile range, 24.4-85.1 months) and 151 deaths (86 RT, 65 CRT). CRT was associated with a 31% reduction in the risk of death (HR = 0.69, 95% CI 0.50-0.95, p = 0.023). We found that CRT was associated with improved OS, compared to RT alone, in patients with non-surgically treated stage I SCCA. These data suggest that de-intensification of therapy in stage I SCCA must be used with caution. However, given the retrospective nature of the data, prospective trials are required.
Project description:BACKGROUND: Oligodendroglial tumors harbor IDH mutations and risk of this type of cancer is associated with a germ-line polymorphism at 8q. In addition, when these tumors harbor a co-deletion of 1p19q, they can be highly chemo-sensitive. Indeed, patients with anaplastic tumors (i.e., AO/AOA) with 1p19q co-deletion lived nearly twice as long after chemotherapy and radiation (CRT; 14-16 years) as radiotherapy alone (RT; 7-9 years) in two large randomized trials. In RTOG 9402, some patients with non-co-deleted AO/AOA also lived longer after CRT: for these participants, the survival curves separated after the median had been reached, and significantly more lived 10 years or longer after CRT than RT (25% vs. 10%). Since co-deletion status did not identify all patients benefiting from CRT, we asked whether other molecular hallmarks of AO/AOA – IDH or G-allele status – might be more inclusive markers of benefit from CRT. METHODS: We used tissues and data from RTOG 9402 to explore this hypothesis. RESULTS: IDH status was evaluable in 210 of 291 participants: 156 (74%) had a mutation of IDH1/2. The G allele of rs55705857 was evaluable in 245 of 291 participants: 76 (31%) carried the risk-allele in their germ-line. Presence of either an IDH mutation or the G risk-allele was associated with significantly longer progression-free survival after CRT, and an IDH mutation with much longer overall survival [9.4 vs. 5.7 years, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.40, 0.86), P = 0.006]. For cases in which IDH was intact, CRT did not prolong median survival time [1.3 vs. 1.8 years, HR 1.14, CI (0.63, 2.04), P = 0.67] or 10-year survival rates (CRT 6% vs. RT 4%). As expected, patients with mutated, co-deleted AO/AOA lived longer after CRT than RT (14.7 vs. 6.8 years, HR 0.49, CI (0.28, 0.85), P = 0.01], but so too did those with mutated, non-co-deleted AO/AOA [5.5 vs. 3.3 years, HR 0.56, CI (0.32, 0.99), P < 0.05]. Among the latter, ATRX positive and negative cases had longer overall survival after CRT than RT, but these differences were not significant. CONCLUSIONS: In AO/AOA cases in RTOG 9402, the presence or risk of an IDH mutation was associated with ‘benefit’ from CRT. Wild-type IDH was associated with poor overall and long-term survival, and absence of benefit from CRT. IDH mutation status identified more patients who benefited from CRT than did 1p/19q co-deletion status, but patients with co-deleted AO/AOA lived much longer.
Project description:Glioblastoma (GBM) is one of the lethal tumors with poor prognosis. However, prognostic prediction approaches need to be further explored. Therefore, we developed an evaluation system that could be used for prognostic prediction of GBM patients. Published mRNA expression datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Chinese Glioma Genome Atlas (CGGA) were analyzed. Quantitative Realtime-PCR of signature genes and molecular aberrations of 178 Xiangya GBM patients were used for confirmation. Gene set enrichment analysis (GSEA) was performed for functional annotation. As a result, we established a 13-gene signature which named Combined Therapy Sensitivity Index (CTSI). Based on a cutoff point, we divided patients into high-risk group and low-risk group. Based on Kaplan-Meier analysis and multivariate Cox regression analysis, we found that patients in the high-risk group had a shorter overall survival time than patients in the low-risk group (p<0.001 in TCGA and CGGA datasets, p=0.047 in GSE4271 dataset, p=0.008 in Xiangya GBM cohort, HR: 1.65-3.42). By comparing the status of IDH mutation, TERT promoter mutation (TERTp-mut) and MGMT promoter methylation, CTSI was predictable in IDH wild-type (IDH-wt)/MGMT promoter unmethylated (MGMTp-unmeth) patients (p=0.037 in IDH-wt/TERTp-mut/MGMTp-unmeth subgroup, HR: 1.98; p=0.032 in IDH-wt/TERTp-wt/MGMTp-unmeth subgroup, HR: 2.09). Based on GESA, the Gene Ontology (GO) gene sets were enriched differently between CTSI high-risk and low-risk groups. Our results showed CTSI risk score can predict the prognosis of IDH-wt/MGMTp-unmeth GBM patients. Based on CTSI, combined with the status of IDH mutation, TERT promoter mutation and MGMT promoter methylation, a stepwise prognosis evaluation system which can provide precise prognosis prediction for GBM patients was established.